COVID-19–associated Lung Microvascular Endotheliopathy: A “From the Bench” Perspective
Authors: Jérémie Joffre, Lauren Rodriguez, Zachary A. Matthay, Elliot Lloyd, Alexander T. Fields, Roland J. Bainton, Philip Kurien, Anita Sil, Carolyn S. Calfee, Prescott G. Woodruff, David J. Erle, Carolyn Hendrickson, Matthew F. Krummel, Charles R. Langelier, Michael A. Matthay, Lucy Z. Kornblith, Judith Hellman, Sharvari Bhide, Carolyn S. Calfee, Sidney A. Carrillo, Suzanna Chak, David J. Erle, Gabriela K. Fragiadakis, Rajani Ghale, Jeremy Giberson, Pat Glenn, Ana Gonzalez, Carolyn Hendrickson, Alejandra Jauregui, Norman Jones, Kirsten Kangelaris, Serena Ke, Matthew F. Krummel, Charles R. Langelier, Tasha Lea, Deanna Lee, Aleskandra Lelidowicz, Raphael Lota, Michael Matthay, Jeff Milush, Viet Nguyen, Ahmad Sadeed Rashid, Nicklaus Rodriguez, Austin Sigman, Kevin Tang, Luz Torres Altamirano, Alyssa Ward, Andrew Willmore, Michael Wilson, Prescott G. Woodruff, Biniam Ambachew, Sarah Cary, Lauren Chalwell, Christopher Colwell, Chayse Jones, Clayton Josephy, Carolyn Hendrickson, Deanna Lee, Matthieu LeGrand, Juan Carlos Montoy, Aaron E. Kornblith, Philip Kurien, Brenda Nunez-Garcia, Viet Nguyen, John J. Park, Arun Prakash, Brittany Robinson, India Shelley, Katherine D. Wick
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Autopsy and biomarker studies suggest that endotheliopathy contributes to coronavirus disease (COVID-19)-associated acute respiratory distress syndrome. However, the effects of COVID-19 on the lung endothelium are not well defined. We hypothesized that the lung endotheliopathy of COVID-19 is caused by circulating host factors and direct endothelial infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Objectives: We aimed to determine the effects of SARS-CoV-2 or sera from patients with COVID-19 on the permeability and inflammatory activation of lung microvascular endothelial cells. Methods: Human lung microvascular endothelial cells were treated with live SARS-CoV-2; inactivated viral particles; or sera from patients with COVID-19, patients without COVID-19, and healthy volunteers. Permeability was determined by measuring transendothelial resistance to electrical current flow, where decreased resistance signifies increased permeability. Inflammatory mediators were quantified in culture supernatants. Endothelial biomarkers were quantified in patient sera. Measurements and Main Results: Viral PCR confirmed that SARS-CoV-2 enters and replicates in endothelial cells. Live SARS-CoV-2, but not dead virus or spike protein, induces endothelial permeability and secretion of plasminogen activator inhibitor 1 and vascular endothelial growth factor. There was substantial variability in the effects of SARS-CoV-2 on endothelial cells from different donors. Sera from patients with COVID-19 induced endothelial permeability, which correlated with disease severity. Serum levels of endothelial activation and injury biomarkers were increased in patients with COVID-19 and correlated with severity of illness. Conclusions: SARS-CoV-2 infects and dysregulates endothelial cell functions. Circulating factors in patients with COVID-19 also induce endothelial cell dysfunction. Our data point to roles for both systemic factors acting on lung endothelial cells and viral infection of endothelial cells in COVID-19–associated endotheliopathy.